TY - JOUR
T1 - Human Pancreatic Carcinoma Cells Activate Maspin Expression Through Loss of Epigenetic Control
AU - Fitzgerald, Matthew
AU - Oshiro, Marc
AU - Holtan, Nicholas
AU - Krager, Kimberly
AU - Cullen, Joseph J.
AU - Futscher, Bernard W.
AU - Domann, Frederick E.
N1 - Funding Information:
Address all correspondence to: Frederick E. Domann, Free Radical and Radiation Biology Program, B180 Medical Laboratories, The University of Iowa, Iowa City, IA 52242, USA. E-mail: [email protected] 1This work was supported, in part, by National Institutes of Health grants to F.E.D. and B.W.F., as well as an institutional grant from the Holden Comprehensive Cancer Center at The University of Iowa. M.O. and K.K. were supported by training grants from the National Cancer Institute. Received 11 August 2003; Revised 29 August 2003; Accepted 4 September 2003.
PY - 2003
Y1 - 2003
N2 - The maspin gene is not expressed in normal human pancreas, but its expression is acquired during human pancreatic carcinogenesis. In other normal human cells and their malignant counterparts, maspin expression is controlled through the epigenetic state of its promoter. In studies presented herein, we used bisulfite genomic sequencing and chromatin immunoprecipitation studies to show that maspin-negative pancreas cells have a methylated maspin promoter, and that the associated H3 and H4 histones are hypoacetylated. In contrast to normal pancreas, four of six human pancreatic carcinoma cell lines investigated displayed activation of maspin expression. This activation of maspin expression in pancreatic carcinoma cells was linked to demethylated promoters and hyperacetylation of the associated H3 and H4 histones. In addition, 5-aza-2′-deoxycytidine treatments activated maspin expression in the two maspin-negative pancreatic carcinoma cell lines, suggesting a causal role for cytosine methylation in the maintenance of a transcriptionally silent maspin gene. Thus, human pancreatic carcinoma cells acquire maspin expression through epigenetic derepression of the maspin locus, and in so doing appear to co-opt a normal cellular mechanism for the regulation of this gene.
AB - The maspin gene is not expressed in normal human pancreas, but its expression is acquired during human pancreatic carcinogenesis. In other normal human cells and their malignant counterparts, maspin expression is controlled through the epigenetic state of its promoter. In studies presented herein, we used bisulfite genomic sequencing and chromatin immunoprecipitation studies to show that maspin-negative pancreas cells have a methylated maspin promoter, and that the associated H3 and H4 histones are hypoacetylated. In contrast to normal pancreas, four of six human pancreatic carcinoma cell lines investigated displayed activation of maspin expression. This activation of maspin expression in pancreatic carcinoma cells was linked to demethylated promoters and hyperacetylation of the associated H3 and H4 histones. In addition, 5-aza-2′-deoxycytidine treatments activated maspin expression in the two maspin-negative pancreatic carcinoma cell lines, suggesting a causal role for cytosine methylation in the maintenance of a transcriptionally silent maspin gene. Thus, human pancreatic carcinoma cells acquire maspin expression through epigenetic derepression of the maspin locus, and in so doing appear to co-opt a normal cellular mechanism for the regulation of this gene.
KW - Cancer
KW - DNA methylation
KW - Gene expression
KW - Histone acetylation
KW - Tumor suppressor gene
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U2 - 10.1016/s1476-5586(03)80045-3
DO - 10.1016/s1476-5586(03)80045-3
M3 - Article
C2 - 14670180
AN - SCOPUS:0344827241
SN - 1522-8002
VL - 5
SP - 427
EP - 436
JO - Neoplasia
JF - Neoplasia
IS - 5
ER -